RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population

Abstract

Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.

RNF213variation, a broader role in neurovascular disease in Caucasian and Japanese populations

“…We have shown, in CEU population, that SLC26A11 rs6565653 tags the RNF213 rs12944088 (p.H4691R) variant. Interestingly, this variant has a MAF of 0.0159 in Caucasian population and was found to be more frequent among subjects with IA (0.0365) than in healthy controls (0.0163) in the French-Canadian IA study (Zhou et al 2016). However, this result was not observed in the JPT population, because most of the variation in the RNF213 gene seems to be specific to a given ethnic background.…”

“…Furthermore, this study found that ICAS patients with the common RNF213 variant were younger than those without the variant and hypothesized that this variant could lead to vascular fragility in a subset of patients, resulting in ischemic and hemorrhagic neurovascular presentations (Bang et al 2016). Studies performed in the French-Canadian population suggest that variation in RNF213 is also a risk factor for developing intracranial aneurysms (IA) (Zhou et al 2016).…”

Distribution of Intracranial Major Artery Stenosis/Occlusion According to RNF213 Polymorphisms

“…Beyond conflicting reports regarding the functional role of RNF213, epidemiologic data have shown significant associations between RNF213 variants and intracranial vascular disorders including MMD, ICASO, cerebral artery dissection, and intracranial aneurysm [4,[24][25][26]. At least 24 genetic changes in RNF213 have been associated with MMD [21].…”

Genetic architecture and adaptations of Nunavik Inuit

“…To test the risk of IA in Nunavik Inuit-specific genetic loci, we performed association tests on 8,291 coding region enriched variants identified with PBS > 0.1 in 42 unadmixed Nunavik IA cases and 62 unadmixed Nunavik controls by using a linear mixed model that accounted for individual relatedness (42). The diagnosis of IA in Inuit was described in our previous study (43). After Bonferroni correction, genomewide significance was set to P < 6.03 × 10 −6 .…”